There are eight thermosensitive TRP channels in mammals, and there might be other TRP channels sensitive to temperature stimuli. Here we demonstrate that TRPM2 can be activated by exposure to warm temperatures (>35°C) apparently via direct heat-evoked channel gating. β-NAD+- or ADP-ribose-evoked TRPM2 activity is robustly potentiated at elevated temperatures. We also show that, even though cyclic ADP-ribose does not activate TRPM2 at 25°C, co-application of heat and intracellular cyclic ADP-ribose dramatically potentiates TRPM2 activity. Heat and cyclic ADP-ribose evoke similar responses in rat insulinoma RIN-5F cells, which express TRPM2 endogenously. In pancreatic islets, TRPM2 is co-expressed with insulin, and mild heating of these cells evokes increases in both cytosolic Ca2+ and insulin release which is KATP channel-independent and protein kinase A-mediated. Heat-evoked responses in both RIN-5F cells and pancreatic islets are significantly diminished by treatment with TRPM2-specific siRNA. These results identify TRPM2 as a potential molecular target for cyclic ADP-ribose, and suggest that TRPM2 regulates Ca2+ entry into pancreatic β-cells at body temperature depending on production of cyclic ADP-ribose-related molecules, thereby regulating insulin secretion.
EMBO J 25 (9): 1804-1815, 2006.
